tbuckley/cabot-search huggingface dataset:
Quality research needs good working conditions
Authors: Rima-Maria Rahal, Susann Fiedler, Adeyemi Adetula, Ronnie P.-A. Berntsson, Ulrich Dirnagl, Gordon B. Feld, Christian J. Fiebach, Samsad Afrin Himi, Aidan J. Horner, Tina B. Lonsdorf, Felix Schönbrodt, Miguel Alejandro A. Silan, Michael Wenzler, Flávio Azevedo
Journal: Nature Human Behaviour (2023)
Doctors are being hamstrung by toxic cultures that damage them and the care they’re able provide
Authors: Jo Wren
Journal: BMJ (2023)

Doctors are being hamstrung by toxic cultures that damage them and the care they're able provide Compassionate, inclusive environments deliver better outcomes for patients Jo Wren head of GMC LondonThe medical workforce is fantastically diverse, benefitting from professionals of all different backgrounds, ethnicities, and cultures.This is especially true in London, where I'm head of the General Medical Council's (GMC) regional outreach team.
An engaged and empowered SAS workforce will provide vital capacity in the current workforce crisis
Authors: Vaishali Parulekar, Vinita Shekar
Journal: BMJ (2023)

We welcome the long awaited Medical Workforce Race Equality Standard (MWRES) First Five report. 1 Race inequality and discrimination within the NHS have been acknowledged in many national surveys and reports.As stated in the MWRES report, time has come for commitment and action from all stakeholders in senior management positions within the NHS to influence change in the workplace.The communication and collaboration between senior NHS Leaders and SAS leaders within the Academy of Medical Royal Colleges (AoMRC) will play a crucial role in future planning and implementation of any proposed changes.
Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer
Authors: Cecilia Monge, Changqing Xie, Yuta Myojin, Kelley Coffman, Donna Mabry Hrones, Sophie Wang, Jonathan M Hernandez, Bradford J Wood, Elliot B Levy, Israa Juburi, Stephen M Hewitt, David E Kleiner, Seth M Steinberg, William D Figg, Bernadette Redd, Philip Homan, Maggie Cam, Benjamin Ruf, Austin G Duffy, Tim F Greten
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Oncolytic immunotherapy represents a unique therapeutic platform for the treatment of cancer. Here, we evaluated the safety and efficacy of the combination of pexastimogene devacirepvec (PexaVec) plus durvalumab (anti-programmed death ligand 1) with and without tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4) in patients with standard chemotherapy refractory mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) in a phase I/II trial. Methods Adult patients with histologically confirmed advanced pMMR mCRC, who had progressed on at least two prior lines of systemic chemotherapy were studied in four cohorts. Patients received four doses of PexaVec IV at a dose of 3×10 8 plaque forming units (pfu) (dose level 1) or 1×10 9 pfu (dose level 2) every 2 weeks. Twelve days after the first PexaVec administration, patients received either 1500 mg of durvalumab every 28 days alone or an additional single dose of 300 mg tremelimumab on day 1. Responses were assessed every 8 weeks by CT or MRI. AEs were recorded. The primary endpoints were safety and feasibility. Secondary endpoints included progression-free survival (PFS) and overall survival. Paired tumor samples and peripheral blood were collected to perform immune monitoring. Results Thirty-four patients with mCRC enrolled on to the study: 16 patients in the PexaVec/durvalumab cohorts and 18 patients in the PexaVec/durvalumab/tremelimumab cohorts. Overall, the combination of PexaVec plus immune checkpoint inhibitors did not result in any unexpected toxicities. Most common toxicities observed were fever and chills after PexaVec infusion. Two cases of grade 3 colitis, one case of a grade 2 myositis and one case of grade 3 hypotension resulted in discontinuation of immune checkpoint inhibitor and PexaVec treatment, respectively. The median PFS in the PexaVec/durvalumab/tremelimumab cohorts was 2.3 months (95% CI: 2.2 to 3.2 months) vs 2.1 months (95% CI: 1.7 to 2.8 months; p=0.57) in the PexaVec/durvalumab cohorts. Flow cytometry analysis of peripheral blood mononuclear cells revealed an increase in Ki67 + CD8 + T cells on treatment. Conclusion PexaVec in combination with durvalumab and tremelimumab is safe and tolerable. No unexpected toxicities were observed. The combination of PexaVec/durvalumab/tremelimumab demonstrated potential clinical activity in patients with pMMR mCRC, but further studies are needed to identify the predictive biomarkers. Trial registration number NCT03206073 .
MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells
Authors: Yoshihiro Morimoto, Nami Yamashita, Tatsuaki Daimon, Haruka Hirose, Shizuka Yamano, Naoki Haratake, Satoshi Ishikawa, Atrayee Bhattacharya, Atsushi Fushimi, Rehan Ahmad, Hidekazu Takahashi, Olga Dashevsky, Constantine Mitsiades, Donald Kufe
Journal: Journal for ImmunoTherapy of Cancer (2023)

The MUC1-C protein evolved in mammals to protect barrier tissues from loss of homeostasis; however, MUC1-C promotes oncogenesis in association with chronic inflammation. Aberrant expression of MUC1-C in cancers has been linked to depletion and dysfunction of T cells in the tumor microenvironment. In contrast, there is no known involvement of MUC1-C in the regulation of natural killer (NK) cell function.Targeting MUC1-C genetically and pharmacologically in cancer cells was performed to assess effects on intracellular and cell surface expression of the MHC class I chain-related polypeptide A (MICA) and MICB ligands. The MICA/B promoters were analyzed for H3K27 and DNA methylation. Shedding of MICA/B was determined by ELISA. MUC1-C interactions with ERp5 and RAB27A were assessed by coimmunoprecipitation and direct binding studies. Exosomes were isolated for analysis of secretion. Purified NK cells were assayed for killing of cancer cell targets.Our studies demonstrate that MUC1-C represses expression of the MICA and MICB ligands that activate the NK group 2D receptor. We show that the inflammatory MUC1-C→NF-κB pathway drives enhancer of zeste homolog 2-mediated and DNMT-mediated methylation of the MICA and MICB promoter regions. Targeting MUC1-C genetically and pharmacologically with the GO-203 inhibitor induced intracellular and cell surface MICA/B expression but not MICA/B cleavage. Mechanistically, MUC1-C regulates the ERp5 thiol oxidoreductase that is necessary for MICA/B protease digestion and shedding. In addition, MUC1-C interacts with the RAB27A protein, which is required for exosome formation and secretion. As a result, targeting MUC1-C markedly inhibited secretion of exosomes expressing MICA/B. In concert with these results, we show that targeting MUC1-C promotes NK cell-mediated killing.These findings uncover pleotropic mechanisms by which MUC1-C confers evasion of cancer cells to NK cell recognition and destruction.
Longitudinal comparison of the developing gut virome in infants and their mothers
Authors: William A. Walters, Andrea C. Granados, Catherine Ley, Scot Federman, Doug Stryke, Yale Santos, Thomas Haggerty, Alicia Sotomayor-Gonzalez, Venice Servellita, Ruth E. Ley, Julie Parsonnet, Charles Y. Chiu
Journal: Cell Host & Microbe (2023)

The human gut virome and its early life development are poorly understood. Prior studies have captured single-point assessments with the evolution of the infant virome remaining largely unexplored. We performed viral metagenomic sequencing on stool samples collected longitudinally from a cohort of 53 infants from age 2 weeks to 3 years (80.7 billion reads), and from their mothers (9.8 billion reads) to examine and compare viromes. The asymptomatic infant virome consisted of bacteriophages, nonhuman dietary/environmental viruses, and human-host viruses, predominantly picornaviruses. In contrast, human-host viruses were largely absent from the maternal virome. Previously undescribed, sequence-divergent vertebrate viruses were detected in the maternal but not infant virome. As infants aged, the phage component evolved to resemble the maternal virome, but by age 3, the human-host component remained dissimilar from the maternal virome. Thus, early life virome development is determined predominantly by dietary, infectious, and environmental factors rather than direct maternal acquisition.
Deficient butyrate-producing capacity in the gut microbiome is associated with bacterial network disturbances and fatigue symptoms in ME/CFS
Authors: Cheng Guo, Xiaoyu Che, Thomas Briese, Amit Ranjan, Orchid Allicock, Rachel A. Yates, Aaron Cheng, Dana March, Mady Hornig, Anthony L. Komaroff, Susan Levine, Lucinda Bateman, Suzanne D. Vernon, Nancy G. Klimas, Jose G. Montoya, Daniel L. Peterson, W. Ian Lipkin, Brent L. Williams
Journal: Cell Host & Microbe (2023)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained debilitating fatigue, cognitive dysfunction, gastrointestinal disturbances, and orthostatic intolerance. Here, we report a multi-omic analysis of a geographically diverse cohort of 106 cases and 91 healthy controls that revealed differences in gut microbiome diversity, abundances, functional pathways, and interactions. Faecalibacterium prausnitzii and Eubacterium rectale, which are both recognized as abundant, health-promoting butyrate producers in the human gut, were reduced in ME/CFS. Functional metagenomics, qPCR, and metabolomics of fecal short-chain fatty acids confirmed a deficient microbial capacity for butyrate synthesis. Microbiome-based machine learning classifier models were robust to geographic variation and generalizable in a validation cohort. The abundance of Faecalibacterium prausnitzii was inversely associated with fatigue severity. These findings demonstrate the functional nature of gut dysbiosis and the underlying microbial network disturbance in ME/CFS, providing possible targets for disease classification and therapeutic trials.
The human inactive X chromosome modulates expression of the active X chromosome
Authors: Adrianna K San Roman, Alexander K Godfrey, Helen Skaletsky, Daniel W Bellott, Abigail F Groff, Hannah L Harris, Laura V Blanton, Jennifer F Hughes, Laura Brown, Sidaly Phou, Ashley Buscetta, Paul Kruszka, Nicole Banks, Amalia Dutra, Evgenia Pak, Patricia C Lasutschinkow, Colleen Keen, Shanlee M Davis, Nicole R Tartaglia, Carole Samango-Sprouse, Maximilian Muenke, David C Page
Journal: Cell Genomics (2023)

The "inactive" X chromosome (Xi) has been assumed to have little impact, in trans, on the "active" X (Xa). To test this, we quantified Xi and Xa gene expression in individuals with one Xa and zero to three Xis. Our linear modeling revealed modular Xi and Xa transcriptomes and significant Xi-driven expression changes for 38% (162/423) of expressed X chromosome genes. By integrating allele-specific analyses, we found that modulation of Xa transcript levels by Xi contributes to many of these Xi-driven changes (≥121 genes). By incorporating metrics of evolutionary constraint, we identified 10 X chromosome genes most likely to drive sex differences in common disease and sex chromosome aneuploidy syndromes. We conclude that human X chromosomes are regulated both in cis, through Xi-wide transcriptional attenuation, and in trans, through positive or negative modulation of individual Xa genes by Xi. The sum of these cis and trans effects differs widely among genes.
Strategic recommendations from the STARS project to foster academic drug development
Authors: Viktoriia Starokozhko, Anne Heß, Wiebke Löbker, Wolfgang Ballensiefen, Eleonora Agricola, Bettina Ziegele, Marko J. Kallio, Laurence O’Dwyer, Yoana Nuevo, Peter G. M. Mol, Anna M. G. Pasmooij
Journal: Nature Reviews Drug Discovery (2023)
Correction: Phase 2 study of oral thalidomide-cyclophosphamide-dexamethasone for recurrent/refractory adult Langerhans cell histiocytosis
Authors: Ji-nuo Wang, Ting Liu, Ai-lin Zhao, Bo-ju Pan, Jian Sun, Jian Li, Dao-bin Zhou, Xin-xin Cao, Ming-hui Duan
Journal: Leukemia (2023)
Exploiting RIG-I-like receptor pathway for cancer immunotherapy
Authors: Yangfu Jiang, Hongying Zhang, Jiao Wang, Jinzhu Chen, Zeyu Guo, Yongliang Liu, Hui Hua
Journal: Journal of Hematology & Oncology (2023)

RIG-I-like receptors (RLRs) are intracellular pattern recognition receptors that detect viral or bacterial infection and induce host innate immune responses. The RLRs family comprises retinoic acid-inducible gene 1 (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2) that have distinctive features. These receptors not only recognize RNA intermediates from viruses and bacteria, but also interact with endogenous RNA such as the mislocalized mitochondrial RNA, the aberrantly reactivated repetitive or transposable elements in the human genome. Evasion of RLRs-mediated immune response may lead to sustained infection, defective host immunity and carcinogenesis. Therapeutic targeting RLRs may not only provoke anti-infection effects, but also induce anticancer immunity or sensitize "immune-cold" tumors to immune checkpoint blockade. In this review, we summarize the current knowledge of RLRs signaling and discuss the rationale for therapeutic targeting RLRs in cancer. We describe how RLRs can be activated by synthetic RNA, oncolytic viruses, viral mimicry and radio-chemotherapy, and how the RNA agonists of RLRs can be systemically delivered in vivo. The integration of RLRs agonism with RNA interference or CAR-T cells provides new dimensions that complement cancer immunotherapy. Moreover, we update the progress of recent clinical trials for cancer therapy involving RLRs activation and immune modulation. Further studies of the mechanisms underlying RLRs signaling will shed new light on the development of cancer therapeutics. Manipulation of RLRs signaling represents an opportunity for clinically relevant cancer therapy. Addressing the challenges in this field will help develop future generations of cancer immunotherapy.
Off-label chemotherapy use in a military treatment facility
Authors: J. F. Powers, M. B. Osswald
Journal: Journal of Clinical Oncology (2009)

6631 Background: Off-label prescribing of chemotherapeutics is thought to be frequent but scant data exist to quantify its occurrence. The few studies evaluating off-label drug use in oncology show that the frequency ranges from 6.7% to 75%. This is the first known evaluation of oncology prescribing practices in a military treatment facility. Methods: After approval by the institutional review board, all outpatient chemotherapy orders from 2006 given in our clinic were reviewed. The date, drug name, dose, diagnosis, intention of therapy (curative, adjuvant, or palliative), and provider status (staff or fellow) were entered into an Excel spreadsheet. Package inserts for each drug were reviewed to determine if the medication was given on- or off-label. The dates of approval and label updates were further defined from FDA press releases. The percentage of courses and individual doses given off-label were calculated. Results: 186 patient charts were included in the analysis. Of 1,341 courses of chemotherapy, 50.48 % (n = 677) were given off-label. Of 3,299 doses of chemotherapy, 47.9% (1,581) were given off-label. Of the drugs prescribed, the most frequently dosed off-label were fluorouracil (n = 334), capecitabine (n = 229), traztuzumab (n = 123), leucovorin (n = 119), and carboplatin (n = 112). Of the 1,581 doses given off-label, 49% (n = 779) were given adjuvantly, 34% (n = 543) were given palliatively, and 16% (n = 259) were given curatively. Conclusions: Based on the current FDA labeling of chemotherapeutics, nearly half of the doses given in our outpatient clinic were off-label. However, the vast majority of our off-label use, such as adjuvant fluorouracil-based therapy, is considered standard of care and is supported by National Comprehensive Cancer Network practice guidelines and compendium listings. This retrospective analysis adds to the scant literature regarding off-label prescribing practices in oncology. No significant financial relationships to disclose.
Radioiodine therapy in advanced differentiated thyroid cancer: Resistance and overcoming strategy
Authors: Yujia Liu, Jiafeng Wang, Xiaoping Hu, Zongfu Pan, Tong Xu, Jiajie Xu, Liehao Jiang, Ping Huang, Yiwen Zhang, Minghua Ge
Journal: Drug Resistance Updates (2023)

Thyroid cancer is the most prevalent endocrine tumor and its incidence is fast-growing worldwide in recent years. Differentiated thyroid cancer (DTC) is the most common pathological subtype which is typically curable with surgery and Radioactive iodine (RAI) therapy (approximately 85%). Radioactive iodine is the first-line treatment for patients with metastatic Papillary Thyroid Cancer (PTC). However, 60% of patients with aggressive metastasis DTC developed resistance to RAI treatment and had a poor overall prognosis. The molecular mechanisms of RAI resistance include gene mutation and fusion, failure to transport RAI into the DTC cells, and interference with the tumor microenvironment (TME). However, it is unclear whether the above are the main drivers of the inability of patients with DTC to benefit from iodine therapy. With the development of new biological technologies, strategies that bolster RAI function include TKI-targeted therapy, DTC cell Redifferentiation, and Improved Drug Delivery via Extracellular Vesicles (EVs) have emerged. Despite some promising data and early success, overall survival was not prolonged in the majority of patients, and the disease continued to progress. It is still necessary to understand the genetic landscape and signaling pathways leading to iodine resistance and enhance the effectiveness and safety of the RAI sensitization approach. This review will summarize the mechanisms of RAI resistance, predictive biomarkers of RAI resistance, and the current RAI sensitization strategies.
Unveiling uterine aging: Much more to learn
Authors: Yaling Wu, Milu Li, Jinjin Zhang, Shixuan Wang
Journal: Ageing Research Reviews (2023)

Uterine aging is an important factor that impacts fertility, reproductive health, and uterus-related diseases; however, it remains poorly explored. Functionally, these disturbances have been associated with an abnormal hormonal response in the endometrium and decreased endometrial receptivity. Based on emerging evidence, these alterations are mediated via the senescence of endometrial stem cells and impaired decidualization of endometrial stromal cells. Multiple molecular activities may participate in uterine aging, including oxidative stress, inflammation, fibrosis, DNA damage response, and cellular senescence. Over the past decade, several protective strategies targeting these biological processes have afforded promising results, including stem cell therapy, anti-aging drugs, and herbal medicines. However, the currently available evidence is fragmented and scattered. Here, we summarize the most recent findings regarding uterine aging, including functional and structural alterations and potential cellular and molecular mechanisms, and discuss potential protective interventions against uterine aging. Thereby, we hope to provide a comprehensive understanding of the pathophysiological processes and underlying mechanisms associated with uterine aging, as well as improve fecundity and reproductive outcomes in females of advanced reproductive age.
3D genome alterations and editing in pathology
Authors: Eugenia A. Tiukacheva, Sergey V. Ulianov, Anna Karpukhina, Sergey V. Razin, Yegor Vassetzky
Journal: Molecular Therapy (2023)

The human genome is folded into a multi-level 3D structure that controls many nuclear functions including gene expression. Recently, alterations in 3D genome organization were associated with several genetic diseases and cancer. As a consequence, experimental approaches are now being developed to modify the global 3D genome organization and that of specific loci. Here, we discuss emerging experimental approaches of 3D genome editing that may prove useful in biomedicine.
Advances in gene therapy hold promise for treating hereditary hearing loss
Authors: Luoying Jiang, Daqi Wang, Yingzi He, Yilai Shu
Journal: Molecular Therapy (2023)

Gene therapy focuses on genetic modification to produce therapeutic effects or treat diseases by repairing or reconstructing genetic material, thus being expected to be the most promising therapeutic strategy for genetic disorders. Due to the growing attention to hearing impairment, an increasing amount of research is attempting to utilize gene therapy for hereditary hearing loss (HHL), an important monogenic disease and the most common type of congenital deafness. Several gene therapy clinical trials for HHL have recently been approved, and, additionally, CRISPR-Cas tools have been attempted for HHL treatment. Therefore, in order to further advance the development of inner ear gene therapy and promote its broad application in other forms of genetic disease, it is imperative to review the progress of gene therapy for HHL. Herein, we address three main gene therapy strategies (gene replacement, gene suppression, and gene editing), summarizing the strategy that is most appropriate for particular monogenic diseases based on different pathogenic mechanisms, and then focusing on their successful applications for HHL in preclinical trials. Finally, we elaborate on the challenges and outlooks of gene therapy for HHL. Gene therapy focuses on genetic modification to produce therapeutic effects or treat diseases by repairing or reconstructing genetic material, thus being expected to be the most promising therapeutic strategy for genetic disorders. Due to the growing attention to hearing impairment, an increasing amount of research is attempting to utilize gene therapy for hereditary hearing loss (HHL), an important monogenic disease and the most common type of congenital deafness. Several gene therapy clinical trials for HHL have recently been approved, and, additionally, CRISPR-Cas tools have been attempted for HHL treatment. Therefore, in order to further advance the development of inner ear gene therapy and promote its broad application in other forms of genetic disease, it is imperative to review the progress of gene therapy for HHL. Herein, we address three main gene therapy strategies (gene replacement, gene suppression, and gene editing), summarizing the strategy that is most appropriate for particular monogenic diseases based on different pathogenic mechanisms, and then focusing on their successful applications for HHL in preclinical trials. Finally, we elaborate on the challenges and outlooks of gene therapy for HHL.